FGF-dependent regulation of VEGF receptor 2 expression in mice
Masahiro Murakami, … , Brian L. Black, Michael Simons
Masahiro Murakami, … , Brian L. Black, Michael Simons
Published June 1, 2011
Citation Information: J Clin Invest. 2011;121(7):2668-2678. https://doi.org/10.1172/JCI44762.
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Research Article Vascular biology Article has an altmetric score of 6

FGF-dependent regulation of VEGF receptor 2 expression in mice

Abstract

Numerous studies have suggested a link between the angiogenic FGF and VEGF signaling pathways; however, the nature of this link has not been established. To evaluate this relationship, we investigated VEGF signaling in ECs with disrupted FGF signaling in vitro and in vivo. ECs lacking FGF signaling became unresponsive to VEGF, caused by downregulation of VEGF receptor 2 (VEGFR2) expression after reduced Vegfr2 enhancer activation. FGF mediated VEGFR2 expression via activation of Erk1/2. Transcriptional analysis revealed that Ets transcription factors controlled VEGFR2 expression in an FGF- and Erk1/2-dependent manner. Mice with defective FGF signaling exhibited loss of vascular integrity and reduced vascular morphogenesis. Thus, basal FGF stimulation of the endothelium is required for maintenance of VEGFR2 expression and the ability to respond to VEGF stimulation and accounts for the hierarchic control of vascular formation by FGFs and VEGF.

Authors

Masahiro Murakami, Loc T. Nguyen, Kunihiko Hatanaka, William Schachterle, Pei-Yu Chen, Zhen W. Zhuang, Brian L. Black, Michael Simons

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Figure 4

Postischemic neovascularization is impaired in Ad–sFGFR1-IIIc–transduced mice.

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Postischemic neovascularization is impaired in Ad–sFGFR1-IIIc–transduced...
(A) Laser Doppler analysis of hindlimb perfusion. Ad-Null, Ad–sFGFR1-IIIc, or Ad–sFGFR3-IIIb (5 × 1010 viral particle in all cases) was injected 7 days prior to the induction of hindlimb ischemia (n = 6 per group). Changes in perfusion are shown as a ratio of right to left hindlimb (R/L). Data (mean ± SEM) were analyzed by Student’s t test. (B) Micro-CT reconstruction at 16-μm resolution of the calf portions of a mouse hindlimb 21 days after femoral artery ligation. Scale bar: 273 μm × 52 μm. (C) Quantitative analysis of micro-CT images in the calf, presented as total number of vascular structures in 250 z axis slices (n = 4 per group). Data are mean ± SEM. (D) SDF-1α expression in the small arteries of the ischemic region. Hindlimb ischemia was induced in control and Ad–sFGFR1-IIIc–transduced mice; 48 hours later, gastrocnemius muscle of the ischemic and nonischemic leg was harvested and subjected to immunostaining for SDF-1α and α-SMA. Scale bars: 20 μm. (E) Quantitative real-time PCR analysis of Vegfr2 expression using total RNA isolated from muscle tissues of C57BL/6 mice injected with Ad-Null or Ad–sFGFR1-IIIc 7 days after ischemia induction (n = 3 per group). *P < 0.05, **P < 0.01 versus Ad-Null.